Retinal deficiencies disrupt or interfere with the production, conversion and/or regeneration of 11-cis-retinal, which is a key Vitamin A derivative in the retinoid or visual cycle. 11-Cis-retinal is an endogenous retinoid produced in and by the retinal pigment epithelium (RPE) from the isomerization and oxidation of the all-trans-retinol (Vitamin A derived from the diet). 11-Cis-retinal functions as a chromophore and covalently binds to the protein opsin to form rhodopsin. Vision is initiated when a light photon is captured by 11-cis-retinal, resulting in the isomerization to all-trans-retinal and disassociation from opsin. Vision is sustained by the cycling of all-trans-retinal back into 11-cis-retinal, which occurs by a complex series of biochemical reactions involving multiple enzymes and proteins in the retinoid or visual cycle.
Endogenous retinoid deficiencies, such as those caused by mutations in the genes encoding the enzymes and proteins utilized in the visual cycle or those caused by the aging process, impair the synthesis of 11-cis-retinal, the result of which leads to visual disorders due to the shortage or depletion of 11-cis-retinal.
For example, Leber congenital amaurosis (LCA), a cause of inherited childhood blindness that affects children from birth or shortly thereafter, is associated with an inherited gene mutation in the RPE65 gene which encodes the protein retinal pigment epithelial protein 65 (RPE65) and/or an inherited gene mutation in the LRAT gene which encodes the enzyme lecithin:retinol acetyltransferase (LRAT). RPE65 and LRAT are both critical for the visual cycle. Patients with LCA lack the ability to generate 11-cis-retinal in adequate quantities and therefore suffer from severe vision loss at birth, nystagmus, poor pupillary responses and severely diminished electroretinograms (ERGs).
Mutations in the LRAT or RPE65 genes are also associated with autosomal recessive retinitis pigmentosa (arRP), which is a subset of hereditary retinitis pigmentosa (RP) which is characterized by degeneration of rod and cone photoreceptors. Patients with arRP may lose vision either in childhood or in mid-life. The classic pattern of vision loss includes difficulties with dark adaptation and night blindness in adolescence and loss of mid-peripheral visual field in young adulthood. arRP typically presents itself as primary rod degeneration with secondary degeneration of cones and is thus described as a rod-cone dystrophy, with rods being more affected than cones. This sequence of the photoreceptor cells involvement explains why arRP patients initially exhibit night blindness, and only in later life become visually impaired in diurnal conditions (Hamel C., Orphanet Journal of Rare Diseases I:40 (2006)). arRP is the diagnosis given to patients with photoreceptor degeneration who have good central vision within the first decade of life, although arRP onset can also occur much later at either the beginning of mid-life or after mid-life (“late onset arRP”). As the disease progresses, patients lose far peripheral vision, eventually develop tunnel vision, and finally lose central vision by the age of 60 years.
Retinitis Punctata Albesciens is another form of Retinitis Pigmentosa that exhibits a shortage of 11-cis-retinal in the rods. Aging also leads to the decrease in night vision and loss of contrast sensitivity due to a shorting of 11-cis retinal. Excess unbound opsin is believed to randomly excite the visual transduction system. This can create noise in the system, and thus more light and more contrast is necessary to see well.
Congenital Stationary Night Blindness (CSNB) and Fundus Albipunctatus are a group of diseases that are manifested as night blindness, but there is not a progressive loss of vision as in the Retinitis Pigmentosa. Some forms of CSNB are due to a delay in the recycling of 11-cis-retinal. Fundus Albipunctatus until recently was thought to be a special case of CSNB where the retinal appearance is abnormal with hundreds of small white dots appearing in the retina. It has been shown recently that this is also a progressive disease although much slower than Retinitis Pigmentosa. It is caused by a gene defect that leads to a delay in the cycling of 11-cis-retinal.
Endogenous retinoid deficiencies can also be associated with the aging process, even in the absence of inherited gene mutations of the genes encoding the enzymes and proteins utilized in the visual cycle. Age-related visual disorders include, for example, loss of night vision, nyctalopia and contrast sensitivity due to a shortage of 11-cis-retinal. This is consistent with the finding that a dramatic slowing of rod-mediated dark adaptation after light exposure associated with human aging is related to a delayed regeneration of rhodopsin (Jackson, G. R. et al., J. Vision Research 39, 3975-3982 (1999)). In addition, excess unbound opsin (due to 11-cis-retinal shortage) is believed to randomly excite the visual transduction system. This can create noise in the system, and thus necessitates more light and/or more contrast in order to see well.
The use of synthetic retinal derivatives and compositions thereof in methods of restoring or stabilizing photoreceptor function in a vertebrate visual system and in methods of treating age-related retinal dysfunction is disclosed in International Published Patent Application Nos. WO 2004/082622, WO 2006/002097, and WO 2011/034551, and Published U.S. Application Nos. 2004/0242704 and 2010/0035986. A study to evaluate the effects of daily and intermittent dosing of 9-cis-retinyl acetate, a synthetic retinal derivative, in RPE65−/− mice is disclosed in Maeda, T. et al., Investigative Ophthalmology & Visual Science (2009), Vol. 50, No. 9, pp. 4368-4378).
Animal models have shown that synthetic retinoids which are highly-light sensitive compounds are photoisomerized or “bleached” by light from the retina within just a few hours unless the eyes are covered. These studies were conducted with the animals kept in the dark during and following treatment with synthetic retinoids until the evaluation period in order to minimize photoisomerization/bleaching of the synthetic retinoid. Batten M L et al. “Pharmacological and rAAV Gene Therapy Rescue of Viscual Functions in a Blind Mouse Model of Leber Congenital Amaurosis” PLo-S Medicine vol. 2, p. 333 (2005); Margaron, P., Castaner, L., and Narfstrom, K. “Evaluation of Intravitreal cis-Retinoid Replacement Therapy in a Canine Model Of Leber's Congenital Amaurosis” Invest Ophthalmol Vis Sci 2009; 50:E-Abstract 6280; Gearhart P M, Gearhart C, Thompson D A, Petersen-Jones S M. “Improvement of visual performance with intravitreal administration of 9-cis-retinal in Rpe65-mutant dogs” Arch Ophthalmol 2010; 128(11): 1442-8.
Frequent administration of any retinoid to compensate for the bleaching effect implicates the well known toxicity of the retinoid class of the compounds. See, Teelmann, K “Retinoids: Toxicity and Teratogenicity to Date,” Pharmac. Ther., Vol. 40, pp 29-43 (1989); Gerber, L E et al “Changes in Lipid Metabolism During Retinoid Administration” J. Amer. Acad. Derm., Vol. 6, pp 664-74 (1982); Allen L H “Estimating the Potential for Vit A Toxicity in Women and Young Children” J. Nutr., Vol. 132, pp. 2907-19 (2002); Silverman, A K “Hypervitaminosis A Syndrome: A Paradigm of Retinoid Side Effects”, J. Am. Acad. Derm., Vol. 16, pp 1027-39 (1987); Zech L A et al. “Changes in Plasma Cholesterol and Triglyceride Levels After Treatment with Oral Isotretinoin” Arch. Dermatol., Vol. 119, pp 987-93 (1983). Toxicity caused by chronic administration of retinoids can cause changes in lipid metabolism, damage to the liver, nausea, vomiting, blurred vision, damage to bones, interference with bone development and several other serious undesirable effects.
In the context of treating the loss or impairment of vision due to retinoid deficiency, which is a chronic condition requiring lifetime treatments, these toxic effects can be very important. These side effects are of particular concern in young patients, whose susceptibility to side effects related to their physical development is well documented.
This combination of a need for repeated administration in response to bleaching, and the undesirable serious side effects of repeated administration, poses a problem for the use of synthetic retinoids to treat the loss of vision caused by retinoid deficiency. A recent study evaluated the usefulness of retinoids as a treatment for these disorders and concluded that retinoids and similar compounds are simply not good clinical candidates for the treatment of retinoid deficiency disorders. See, Fan J. et al. “Light Prevents Exogenous 11-cis Retinal from Maintaining Cone Photoreceptors in Chromophore-deficient Mice”, Invest. Ophthalmol. Vis Sci. Jan. 12, 2011, 10-6437.
It has now been discovered that by use of certain dosing regimens of synthetic retinal derivatives, it is possible to produce meaningful improvement or recovery of vision that is long lasting, while chronic toxic effects can be greatly reduced or even eliminated. This was completely unexpected, and indeed is completely contrary to the expectation of the art.